Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients with pruritic (itchy) blisters should alert the physician. The disease onset can be in adulthood or in childhood, even in the neonate. The disease onset in childhood has been termed chronic bullous dermatosis of childhood, which is now considered to be the same disease as LABD in adulthood.

Characteristic findings on physical examination

The most useful finding is a group of blisters lining up in a circle, creating a “string of pearls” configuration (Figure 1). However, patients suffering from a vancomycin-induced form of LABD may resemble morbilliform eruption, erythema multiforme, Stevens-Johnson syndrome, or toxic epdiermal necrolysis clinically. The patient afflicted with a phenytoin-induced form of LABD may also resemble toxic epidermal necrolysis.

Diagnosis confirmation

Histologic differential diagnoses: The histopathologic findings of subepidermal blister with prominent neutrophil infiltration can also be observed in dermatitis herpetiformis, epidermolysis bullosa acquisita, bullous lupus erythematosus and two partially characterized autoimmune blistering skin diseases: anti-p105 pemphigoid and anti-p200 pemphigoid. ELISA testing for autoantibodies present in linear IgA dermatosis is currently not available on a commercial basis.

Who is at Risk for Developing this Disease?

As a rare disease, LABD is observed in patients of all races and genders. Accurate epidemiologic data for LABD is currently not available. Many drug-induced cases have been reported. The drug-induced form of disease is commonly due to vancomycin. Other reported cases are apparently associated with other antibiotics, phenytoin, angiotensin-converting enzyme inhibitor, acetaminophen, carbamazepine, naproxen, and piroxicam.

A study has reported a significant association of HLA Cw7, B8, and DR3 with the disease.

What is the Cause of the Disease?

Etiology:

The disease is mediated by IgA class autoantibodies targeting one of the many skin epithelial basement membrane proteins named BP180 (type XVII collagen); its antigenic epitope is located in the upper/mid-lamina lucida level.

Pathophysiology

It is commonly hypothesized that the IgA autoantibodies bind to the target antigen in the lamina lucida, leading to complement activation, followed by chemoattraction of neutrophils into the target site. The subsequent release of enzymes by the reactive neutrophils may lead to the weakening of the binding structure of lamina lucida, resulting in clefting between the epidermis and dermis leading to the formation of a subepidermal blister. The pathogenesis of the IgA autoantibodies, ie, how the autoantibodies come about, however, is not understood at the present time.

Systemic Implications and Complications

It is now recognized that some inflammatory diseases (such as coeliac disease, inflammatory bowel disease, IgA nephropathy), internal malignancies (such as renal cell carcinoma, leukemia) and monoclonal gammopathy are associated with the onset of LABD. However, these associations randomly occur without any particular HLA pattern identified. Thus, physicians who care for patients suffering from LABD should perform a careful review of systems and order appropriate laboratory studies (CBC, urinalysis) or refer to appropriate specialists when indicated. A full physical examination by the patient's primary care physician is recommended.

Treatment Options

MEDICAL TREATMENT FOR ADULT PATIENTS:

Topical: Topical corticosteroids may be used as an adjunct treatment for LABD.

Systemic

Most patients affected by LABD require systemic treatment. The initial treatment regimen should be dapsone, with an average dose of 100mg per day. In some cases, a low dose (10 to 20mg per day) of systemic corticosteroids (prednisone) is also needed to control the disease. In case dapsone treatment results in intolerable side effects (such as peripheral neuropathy or a low red-cell count), it can be substituted with other sulfur-containing medication (such as trimethoprim/sulfamethoxazole).

The next treatment option would be mycophenolate mofetil. Other successful treatments reported in the literature include cyclosporin, colchicine, and intravenous immunoglobulin G (IVIG). If the patient fails to respond completely, rituximab (anti-B cell antibody) in combination with IVIG would be a good option.

MEDICAL TREATMENT FOR PEDIATRIC PATIENTS

In general the dose must be carefully adjusted according to the age or weight of the patients. Topical corticosteroids, if used, must be used for short-term only to avoid the skin thinning effect of corticosteroid on immature skin.

Dapsone should be initiated unless otherwise contraindicated. Colchicine should be tried if dapsone is not tolerated or if it is contraindicated (as in G6PD-deficiency or drug allergy). Other drugs from the sulfa group can be tried as well, such as sulfapyridine, trimethoprim/sulfamethoxazole. Rare reports of successful treatment with dicloxacillin provide yet another option. Erythromycin is somewhat effective, but sustained improvement has not been the outcome.

Systemic corticosteroids or other immunosuppressives (such as mycophenolate mofetil) should be used only if other medications failed in cases of generalized disease; these agents should be used with the full consent from the patients' pediatricians.

Rituximab, an antibody against a B-cell surface marker, CD20, is an option that should be used only if all other medications failed in cases of generalized disease.

SURGICAL TREATMENT: None available.

PHYSICAL MODALITIES: None available.

Optimal Therapeutic Approach for this Disease

LOCALIZED LABD

Topical corticosteroids (mid to high potency) should be initiated. For adult patients, medium to high potency corticosteroid could be used. One good choice would be betamethasone diproprionate 0.05% cream twice daily. For pediatric patients, low-to-medium potency corticosteroid would be a better choice, such as mometasone furoate 0.1% cream twice daily. If the disease is not completely controlled, the addition of dapsone (50 to 100mg per day, adult dose) may be sufficient.

GENERALIZED LABD

Stop any offending agents. Initial treatment option will be dapsone (50 to 100 mg per day, adult dose). Since the histologic finding of LABD is characteristic of neutrophil infiltration and dapsone has direct antagonistic effect on neutrophils, this is the first line of treatment. If dapsone treatment results in intolerable side effects, substitution with another sulfur-containing medication is appropriate, since other sulfur medications also possess antagonistic effects to neutrophils. One option is trimethoprim-sulfamethoxasole (Bactrim), double strength, twice daily. Sulfapyridine or sulfasalazine are other sulfa-containing medications that could be beneficial, but their availability in the United States is unreliable.

If dapsone or a sulfur-containing medication alone does not completely control the disease, the addition of low dose prednisone (10 to 20mg per day, adult dose) would be appropriate, as it provides an additional anti-inflammatory effect.

In case the combination of low-dose prednisone and dapsone (or other sulfur-containing drug) does not achieve complete control of the disease, the addition of an immunosuppressive agent (azathioprine or mycophenolate mofetil) should be considered. Azathioprine (100mg per day, adult dose) or mycophenolate mofetil (1g per day, adult dose) will be average initial doses for the additional regimen. These immunosuppressives provide direct countering effect to the immune system, for both B and T cells.

Rituximab, an antibody directly against B cells (CD20), is a new treatment, which, although expensive, may be available for those rare cases that are unresponsive to standard treatments (alone or in combination). Rituximab is probably best used in combination with IVIG. One such protocol for adult patients, proven to be useful in treating pemphigus vulgaris, is the following:

Initial courses: For the first two months: Rituximab 375mg/m2 body surface every week for the first three weeks, followed by IVIG 2 g/kg body weight for the fourth week, then this 4-week therapy will be repeated for a second month.

Maintenance courses: For the next 4 months: Rituximab 375mg/m2 body surface one dose per month and IVIG 2g/kg body weight one dose per month.

Other treatment options reported to be useful in only a small number of patients may be considered in individual cases, such as cyclosporine or colchicine.

Patient Management

Patients receiving only topical treatments should be monitored on a monthly basis initially. As the disease resolves, the frequency of patient visits can be reduced to every other month, and then to every 3 months. Physicians need to monitor for possible skin atrophy induced by the chronic use of topical steroids. Thus, the use of a high-potency steroid should be limited in duration and should be changed to medium- or low-potency steroids when clinically appropriate.

Patients receiving prednisone treatment should be monitored for common steroid side effects on a regular basis (at least every other month). The use of prednisone should be restricted to a minimal level for the shortest possible duration. Tapering the prednisone dose should be considered as the disease resolves.

Patients receiving immunosuppressive agents should be monitored for bone marrow suppression on a regular basis, at least every other month. An absolute lymphocyte count usually is the most sensitive parameter in assessing bone marrow suppression by these medications.

Patients receiving azathioprine or mycophenolate mofetil should be monitored for liver toxicity on a regular basis, at least every other month.

Since malignancies have been associated with the onset of LABD, a careful review of systems should be performed regularly in all patients, although thus far these cases were found in adult patients. No single malignancy is seen to be particularly prominent. If a symptom suggests a problem in a particular organ system, appropriate screening diagnostic studies should be requested to investigate the possibility of a malignancy, and referral to the appropriate specialist..

Unusual Clinical Scenarios to Consider in Patient Management

Even though initially chronic bullous dermatosis of childhood was recognized as a disease distinct from the adult form of LABD, it is now understood that these are the same disorder for these four reasons: 1) Both diseases manifest with itchy blisters that tend to form a “string of pearls” pattern; 2) Both diseases manifest histologically as sub-epidermal blister with predominantly neutrophil infiltration; 3) Both diseases are characterized by linear IgA deposition on the skin basement membrane and by circulating IgA autoantibodies that bind to the epidermal side of high salt-split human skin substrate; and 4) Both diseases are characterized by IgA autoantibodies that target the BP180 protein.

Even though association of LABD with internal malignancies is predominantly identified in adult patients with LABD, physicians should be alerted to this possibility when a pediatric patient affected by LABD presents with an unusual symptom or sign suggesting an internal malignancy.

What is the evidence?

Farrant, P, Darley, C, Carmichael, A. "Is erythromycin an effective treatment for chronic bullous disease of childhood? A national survey of members of the British Society for Paediatric Dermatology". Pediatr Dermatol.
vol. 25. 2008. pp. 479-82.

(By survey, among the 40 patients treated in a 2-year period, 5 patients received erythromycin as the first-line drug. Although three of these patients obtained initial improvement or complete resolution, only one of these patients had sustained benefits and the other two patients had their diseases relapsed in 4 to 12 weeks. Thus, erythromycin may be a good initial medication of choice, especially in a clinically supported case awaiting diagnostic test confirmation.)

(In an HLA study of 60 patients [26 had chronic bullous dermatosis of childhood; 34 had adult LABD] using lymphocyte microtoxicity assay, the disease was found to be significantly associated with HLA Cw7 (P=.001), B8 (P=.04), and DR3 (P=.014).

(In a study of 12 sera obtained from patients of chronic bullous dermatosis of childhood, 8 of these sera bound to the epidermal roof of high-salt-split skin substrate also reacted with a 97-kDa protein that co-migrated with a 97-kDa protein reacted by IgA autoantibodies from adult patients affected by LABD, strongly suggesting that the target antigens for both of these forms of disease are the same.)

(An adult patient who failed to respond completely to mycophenolate mofetil and systemic corticosteroid, and was not able to tolerate dapsone, was completely controlled by adding a dose of trimethoprim-sulfamethoxazole.)

(The drug-induced form of LABD can resemble Stevens-Johnson syndrome, thus,physician should be alerted to this possibility, as removal of the offending drug is essential for managing this form of disease.)

(Vancomycin-induced LABD can resemble a life-threatening dermatosis toxic epidermal necrolysis and physicians should be alerted to this possibility and obtain appropriate diagnostic tests such as direct immunofluorescence microscopy to rule out this possibility.)